Introduction
Of the numerous plant psychotropics utilized by indigenous populations of the
Amazon Basin, perhaps none is as interesting or complex, botanically, chemically,
or ethnographically, as the beverage known variously as ayahuasca , caapi, or
yage. The beverage is most widely known as ayahuasca , a Quechua term meaning
"vine of the souls," which is applied both to the beverage itself
and to one of the source-plants used in its preparation, the Malpighiaceous
jungle liana, Banisteriopsis caapi (Schultes, 1957). In Brazil, transliteration
of this Quechua word into Portuguese results in the name, Hoasca . Hoasca, or
ayahuasca , occupies a central position in Mestizo ethnomedicine, and the chemical
nature of its active constituents and the manner of its use makes its study
relevant to contemporary issues in neuropharmacology, neurophysiology, and psychiatry.

Traditional
and Indigenous Uses of Ayahuasca

The use of ayahuasca under a variety of names is a widespread practice among
various indigenous aboriginal tribes endemic to the Amazon Basin (Schultes,
1957). Such practices undoubtedly were well established in pre-Columbian times,
and in fact may have been known to the earliest human inhabitants of the region.
Iconographic depictions on ceramics and other artifacts from Ecuador have provided
evidence that the practice dates to at least 2000 B.C. (Naranjo, 1986). Its
widespread distribution among numerous Amazonian tribes also argues for its
relative antiquity.

Considerable genetic
intermingling and adoption of local customs followed in the wake of European
contact, and ayahuasca , along with a virtual pharmacopoeia of other medicinal
plants, gradually became integrated into the ethnomedical traditions of these
mixed populations. Today the drug forms an important element of ethnomedicine
and shamanism as it is practiced among indigenous Mestizo populations in Peru,
Colombia, and Ecuador. The sociology and ethnography of the contemporary use
of ayahuasca (as it is most commonly termed) in Mestizo ethnomedicine has been
extensively described (Dobkin de Rios, 1972, 1973; Luna, 1984, 1986)

Syncretic
Religious Use of Ayahuasca

From the perspective of the sociologist or the ethnographer, discussion of the
use of ayahuasca or hoasca can conveniently be divided into a consideration
of its use among indigenous aboriginal and mestizo populations, and its more
recent adoption by contemporary syncretic religious movements such as the Uni'
do Vegetal (UDV), Barquena, and Santo Daime sects in Brasil. It is within the
context of acculturated groups such as these that questions regarding the psychological,
medical, and legal aspects of the use of ayahuasca become most relevant, and
also, most accessible to study.

The use of ayahuasca
in the context of mestizo folk medicine closely resembles the shamanic uses
of the drug as practiced among aboriginal peoples. In both instances, the brew
is used for curing, for divination, as a diagnostic tool and a magical pipeline
to the supernatural realm. This traditional mode of use contrasts from the contemporary
use of ayahuasca tea within the context of Brazilian syncretic religious movements.
Within these groups, the members consume ayahuasca tea at regular intervals
in group rituals in a manner that more closely resembles the Christian Eucharist
than the traditional aboriginal use. The individual groups of the UDV, termed
nucleos, are similar to a Christian Hutterite sect, in that each group has a
limited membership, which then splits to form a new group once the membership
expands beyond the set limit. The nucleo consists of the congregation, a group
leader or mestre, various acolytes undergoing a course of study and training
in order to become mestres, and a temple, an actual physical structure where
the sacrament is prepared and consumed at prescribed times, usually the first
and third Saturday of each month. The membership of these newer syncretic groups
spans a broad socio-economic range and includes many educated, middle-class,
urban professionals (including a number of physicians and other health professionals).
Some older members have engaged in the practice for 30 or more years without
apparent adverse health effects.

The UDV and the
Santo Daime sects are the largest and most visible of several syncretic religious
movements in Brasil that have incorporated the use of ayahuasca into their ritual
practices. Of the two larger sects, it is the UDV that possesses the strongest
organizational structure as well as the most highly disciplined membership.
Of all the ayahuasca churches in Brasil, the UDV has also been the most pivotal
in convincing the government to remove ayahuasca from its list of banned drugs.
In 1987, the government of Brasil approved the ritual use of hoasca tea ('hoasca' is
a Portugese shortening of 'ayahuasca' and is sometimes used to differentiate UDV brew
from non-UDV ayahuasca) in the context of group religious ceremonies.
This ruling has potentially significant implications, not only for Brasil, but
for global drug policy, as it marks the first time in over 1600 years that a
government has granted permission to its non-indigenous citizens to use a psychedelic
substance in the context of religious practices.

Botanical,
Chemical, and Pharmacological Aspects of Ayahuasca

Ayahuasca is unique in that its pharmacological activity is dependent on a synergistic
interaction between the active alkaloids in the plants. One of the components,
the bark of Banisteriopsis caapi, contains ß-carboline alkaloids, which
are potent MAO-A inhibitors; the other component, the leaves of Psychotria viridis
or related species, contains the potent short-acting psychoactive agent N,N-dimethyltryptamine
(DMT). DMT is not orally active when ingested by itself, but can be rendered
orally active in the presence of a peripheral MAO inhibitor - and this interaction
is the basis of the psychotropic action of ayahuasca (McKenna, Towers, &
Abbott, 1984).

1 Botanical sources
of ayahuasca

In a traditional context, Ayahuasca is a beverage prepared by boiling - or soaking
- the bark and stems of Banisteriopsis caapi together with various admixture
plants. The admixture employed most commonly is the Rubiaceous genus Psychotria,
particularly P. viridis. The leaves of P. viridis contains alkaloids which are
necessary for the psychoactive effect (see the sections on chemistry and pharmacology,
below). There are also reports (Schultes, 1972) that other Psychotria species,
especially P. leiocarpa or P. carthaginensis, are used instead of P. viridis,
but such reports may be due to a botanical misidentification; in any case, use
of Psychotria species other than P. viridis is rare. In the Northwest Amazon,
particularly in the Colombian Putumayo and Ecuador, the leaves of Diplopterys
cabrerana, a jungle liana in the same family as Banisteriopsis, are added to
the brew in lieu of the leaves of Psychotria. The alkaloid present in Diplopterys,
however, is identical to that in the Psychotria admixtures, and pharmacologically,
the effect is the same. In Peru, various admixtures in addition to Psychotria
or Dipolopterys are frequently added, depending on the magical, medical, or
religious purposes for which the drug is being consumed. Although a virtual
pharmacopoeia of admixtures are occasionally added, the most commonly employed
admixtures (other than Psychotria, which is a constant component of the preparation)
are various Solanaceous genera, including tobacco (Nicotiana sp.), Brugmansia
sp., and Brunfelsia sp. (Schultes, 1972; McKenna, et al., 1995). These Solanaceous
genera are known to contain alkaloids, such as nicotine, scopalamine, and atropine,
which effect both central and peripheral adrenergic and cholinergic neurotransmission.
The interactions of such agents with serotonergic agonists and MAO inhibitors
are essentially unknown in modern medicine.

2 Chemistry of
ayahuasca and its source plants

The chemical constituents of ayahuasca and the source-plants used in its preparation
have been well characterized (McKenna, et al., 1984; Rivier & Lindgren,
1972). Banisteriopsis caapi contains the ß-carboline derivatives harmine,
tetrahydroharmine, and harmaline as the major alkaloids (Callaway, et al., 1996).
Trace amounts of other ß-carbolines have also been reported (McKenna, et
al., 1984; Rivier & Lindgren, 1972; Hashimoto and Kawanishi, 1975, 1976)
as well as the pyrrolidine alkaloids shihunine and dihydroshihunine (Kawanishi
et al. 1982). The admixture plant, Psychotria viridis, contains a single major
alkaloid, N,N-dimethyltryptamine (DMT), while N-methyl tryptamine and methyl-tetrahydro-ß-carboline
have been reported as trace constituents (McKenna, et al., 1984; Rivier &
Lindgren, 1972). The admixture plant Psychotria carthagenensis has been reported
to contain the same alkaloids (Rivier & Lindgren, 1972) but a subsequent
investigation could not confirm the presence of DMT in the single collection
examined (McKenna, et al., 1984). The concentrations of alkaloids reported in
Banisteriopsis caapi range from 0.05 % dry weight to 1.95 % dry weight; in Psychotria,
the concentration of alkaloids ranged from 0.1 to 0.66 % dry weight (McKenna,
et al., 1984; Rivier & Lindgren, 1972). Similar ranges and values were reported
by both groups of investigators.

The concentrations
of alkaloids in the ayahuasca beverages are, not surprisingly, several times
greater than in the source plants from which they are prepared. Based on a quantitative
analysis of the major alkaloids in several samples of ayahuasca collected on
the upper Rio Purs, Rivier & Lindgren (1972) calculated that a 200
ml dose of ayahuasca contained an average of 30 mg of harmine, 10 mg tetrahydroharmine,
and 25 mg DMT. Callaway, et al., determined the following concentrations of
alkaloids in the hoasca tea utilized in the biomedical study with the UDV (mg/ml):
DMT, 0.24; THH, 1.07; harmaline, 0.20; and harmine 1.70. A typical 100 ml dose
of hoasca thus contains in mg: DMT, 24; THH, 107; harmaline, 20; harmine, 170.
Interestingly, these concentrations are above the threshold of activity for
i.v. administration of DMT (Strassman & Qualls, 1994).

McKenna et al.
(1984) reported somewhat higher values for the alkaloid content of several samples
of Peruvian ayahausca. These investigators calculated that a 100 ml dose of
these preparations contained a total of 728 mg total alkaloid, of which 467
mg is harmine, 160 mg is tetrahydroharmine, 41 mg is harmaline, and 60 mg is
DMT. This is well within the range of activity for DMT administered i.m. (Szara,
1956) or i.v. (Strassman & Qualls, 1994) and is also well within the range
for harmine to act effectively as a monoamine oxidase inhibitor (MAOI). In vitro,
these ß-carbolines function as MAOI at approximately 10 nM (e.g., harmine's
IC50 for MAOI is ~1.25 x 10-8 M; cf. McKenna, et al., 1984; Buckholtz &
Boggan, 1977). In mice, harmaline administered i.p. at 5 mg/kg causes 100% inhibition
by 2 hours post-injection, the activity falling off rapidly thereafter (Udenfriend
et al. 1958) This dose corresponds to approximately 375 mg in a 75 kg adult,
but, based on the measured concentration of harmine in the liver, it is likely
that one half this dose or less would also be effective. The reasons for the
discrepancy in alkaloid concentrations between the samples examined by Rivier
& Lindgren (1972) and those examined by McKenna, et al. (1984) are readily
explained by the differences in the methods of preparation. The method employed
in preparing ayahuasca in Pucallpa, Peru, where the samples analyzed by McKenna
et al. (1984) were collected, results in a much more concentrated brew than
the method employed on the upper Rio Purs, the region which was the source
of the samples examined by Rivier & Lindgren. The concentrations and proportions
of alkaloids can vary significantly in different batches of ayahuasca , depending
on the method of preparation, as well as the amounts and proportions of the
source-plants.

ß-carbolines,
by themselves, may have some psychoactivity and thus may contribute to the overall
psychotropic activity of the ayahuasca beverage; however, it is probably inaccurate
to characterize the psychotropic properties of ß-carbolines as "hallucinogenic"
or "psychedelic" (Shulgin & Shulgin, 1997). As MAO inhibitors,
ß-carbolines can increase brain levels of serotonin, and the primarily
sedative effects of high doses of ß-carbolines are thought to result from
their blockade of serotonin deamination. The primary action of ß-carbolines
in the ayahuasca beverage is their inhibition of peripheral MAO, which protects
the DMT in the brew from peripheral degradation and thus renders it orally active.
There is some evidence, however, that tetrahydroharmine (THH), the second most
abundant ß-carboline in the beverage, acts as a weak 5-HT uptake inhibitor
and MAOI. Thus, THH may prolong the half-life of DMT by blocking its intraneuronal
uptake, and hence, its inactivation by MAO, localized in mitochondria within
the neuron. On the other hand, THH may block serotonin uptake into the neuron,
resulting in higher levels of 5HT in the synaptic cleft; this 5-HT, in turn,
may attenuate the subjective effects of orally ingested DMT by competing with
it at post-synaptic receptor sites (Callaway, et al., 1997).

3 Pharmacological
actions of Ayahuasca and its Active Alkaloids

The psychotropic activity of ayahuascais a function of the peripheral inactivation
of MAO by the ß-carboline alkaloids in the mixture. This action prevents
the peripheral oxidative deamination of the DMT, which is the primary psychotropic
component, rendering it orally active and enabling it to reach its site of action
in the CNS in an intact form. (McKenna, et al 1984; Schultes, 1972). DMT alone
is inactive following oral administration at doses up to 1000 mg (Shulgin, 1982;
Nichols, et al. 1991). DMT is active by itself following parenteral administration
starting at around 25 mg (Szara, 1956; Strassman & Qualls, 1994). Because
of its oral inactivity, various methods of parenteral administration are employed
by users. For example, synthetic DMT is commonly smoked as the free base; in
this form, the alkaloid volatilizes readily and produces an immediate, intense
psychedelic episode of short duration (5 -15 min), usually characterized by
multicolored, rapidly moving visual patterns behind the closed eyelids (Stafford,
1977). The Yanomamo Indians and other Amazonian tribes prepare a snuff from
the sap of various trees in the genus Virola, which contain large amounts of
DMT and the related compound, 5-methoxy-DMT, which is also orally inactive (McKenna,
et al. 1985; Schultes and Hofmann, 1980). The effects of the botanical snuffs
containing DMT, while not as intense as smoking DMT free base, are similarly
rapid in onset and of limited duration [unpublished data]. The ayahuasca beverage
is unique in that it is the only traditionally used psychedelic where the enzyme-inhibiting
principles in one plant (ß-carbolines) are used to facilitate the oral
activity of the psychoactive principles in another plant (DMT). The psychedelic
experience which follows ingestion of ayahuasca differs markedly from the effects
of parenterally ingested DMT; the time of onset is approximately 35-40 minutes
after ingestion, and the effects, which are less intense than parenterally administered
synthetic DMT, last approximately four hours. The subjective effects of ayahuasca
include phosphene imagery seen with the eyes closed, dream-like reveries, and
a feeling of alertness and stimulation. Peripheral autonomic changes in blood
pressure, heart-rate, etc., are also less pronounced in ayahuasca than parenteral
DMT. In some individuals, transient nausea and episodes of vomiting occur, while
others are rarely affected in this respect. When ayahuasca is taken in a group
setting, vomiting is considered a normal part of the experience and allowances
are made to accommodate this behavior (Callaway, et al., 1997).

The amounts of
ß-carbolines present in a typical dose of ayahuasca are well above the
threshold for activity as MAOI. It is likely that the main contribution of the
ß-carbolines to the acute effects of ayahuasca results from their facilitation
of the oral activity of DMT, through their action as peripheral MAOI. It is
worthy of note that ß-carbolines are highly selective inhibitors of MAO-A,
the form of the enzyme for which serotonin, and presumably other tryptamines,
including DMT, are the preferred substrates (Yasuhara, et al., 1972; Yasuhara,
1974). This selectivity of ß-carbolines for MAO-A over MAO-B, combined
with their relatively low affinity for liver MAO compared to brain MAO, may
explain why reports of hypertensive crises following the ingestion of ayahuasca
have not been documented. On the other hand, Suzuki, et al., (1981) has reported
that DMT is primarily oxidized by MAO-B; it is possible, therefore, that high
concentrations of ß-carbolines, partially inhibit MAO-B as well as MAO-A;
but the greater affinity of tyramine for MAO-B enables it to compete for binding
to the enzyme and displace any residual ß-carbolines. This mechanism would
explain the lack of any reports of peripheral autonomic stimulation associated
with the ingestion of ayahuasca in combination with foods containing tyramine
(Callaway, et al., 1997).

DMT and its derivatives
and the ß-carboline derivatives are widespread in the plant kingdom (Allen
& Holmstedt, 1980) and both classes of alkaloids have been detected as endogenous
metabolites in mammals, including man (Bloom, et al. 1982; Barker, et al. 1981a;
Airaksinen & Kari, 1981). Methyl transferases which catalyze the synthesis
of DMT, 5-methoxy-DMT, and bufotenine have been characterized in human lung,
brain, blood, cerebrospinal fluid, liver, and heart, and also in rabbit lung,
toad, mouse, steer, guinea pig, and baboon brains, as well as in other tissues
in these species (McKenna & Towers, 1984). Endogenous psychotogens have
been suggested as possible etiological factors in schizophrenia and other mental
disorders, but the evidence remains equivocal (Fischman, 1983). Although the
occurrence, synthesis, and degradative metabolism of DMT in mammalian systems
has been the focus of recent scientific investigations (Barker, et al. 1981b),
the candidacy of DMT as a possible endogenous psychotogen essentially ended
when experiments showed comparable levels in both schizophrenics and normals.
At present the possible neuroregulatory functions of this "psychotomimetic"
compound are incompletely understood, but Callaway (1988) has presented an interesting
hypothesis regarding the possible role of endogenous DMT and ß-carbolines
in regulating sleep cycles and REM states.

ß-carbolines
are tricyclic indole alkaloids that are closely related to tryptamines, both
biosynthetically and pharmacologically. They are readily synthesized via the
condensation of indoleamines with aldehydes or alpha-keto acids, and their biosynthesis
probably also proceeds via similar reactions (Callaway et al., 1994). ß-carbolines
have also been identified in mammalian tissue including human plasma and platelets,
and rat whole brain, forebrain, arcuate nucleus, and adrenal glands (Airaksinen
and Kari, 1981). 6-methoxy-tetrahydro-ß-carboline has been recently identified
as a major constituent of human pineal gland (Langer et al. 1984). This compound
inhibits the high-affinity binding of [3H]-imipramine to 5-HT receptors in human
platelets (Langer et al. 1984), and also significantly inhibits 5-HT binding
to type 1 receptors in rat brain; the compound has a low affinity to type 2
receptors, however (Taylor et al. 1984). 2-methyl-tetrahydro-ß-carboline
and harman have been detected in human urine following ethanol loading, (Rommelspacher,
et al., 1980) and it has been suggested that endogenous ß-carbolines and
other amine-aldehyde condensation products may be related to the etiology of
alcoholism (Rahwan, 1975). At least one ß-carboline has been identified
as a by-product of the oxidative metabolism of DMT in rat brain homogenates
(Barker, et al. 1980).

ß-carbolines
also exhibit other biological activities in addition to their effects on neurophysiological
systems. For instance Hopp and co-workers found that harmine exhibited significant
anti-trypanosomal activity against Trypanosoma lewisii (Hopp et al., 1976).
This finding may explain the use of ayahuasca in mestizo ethnomedicine as a
prophylactic against malaria and internal parasites (Rodriguez, et al. 1982).
Certain ß-carbolines are known to exert mutagenic or co-mutagenic effects,
and the mechanism responsible may be related to their interactions with nucleic
acids (Umezawa, et al. 1978; Hayashi, et al. 1977). The ultra-violet activated
photocytotoxic and photogenotoxic activity of some ß-carbolines has also
been reported (McKenna & Towers 1981; Towers & Abramosky, 1983).

Recent Biomedical
Investigations of Ayahuasca

Although achieving some notoriety in North American literature through the popular
press and the writings of William Burroughs and Allan Ginsberg (Burroughs and
Ginsberg, 1963), the psychological and physiological phenomena induced by ayahuasca
have received little or no rigorous study. Various travellers to the Amazon
have reported their own first hand experiences with ayahuasca (Weil, 1980; Davis,
1996), while both formal and informal ethnographic narratives have excited the
public imagination (Lamb, 1971; Luna and Amaringo, 1991). Interest in the exotic
origins and effects of ayahuasca have attracted a steady stream of North American
tourists, often enticed by articles and advertisements in popular and New Age
magazines (Krajick, 1992; Ott, 1993). Concern over possible adverse health effects
resulting from the use of ayahuasca by such naive travelers has recently been
expressed by a noted authority on Mestizo ayahuasca use (Dobkin de Rios, 1994).
These concerns are in marked contrast to testimonials of improved psychological
and moral functioning by the adherents of the syncretic hoasca churches in Brasil.

The individuals
who are attracted to the UDV seem to belong to a slightly more professional
socio-economic class than those who join the Santo Daime. Of the approximately
7000 members of the UDV in Brasil, perhaps 5 - 10 % are medical professionals,
among them physicians, psychiatrists, psychologists, chiropracters, and homeopathic
physicians. Most of these individuals are fully aware of the psychologically
beneficial aspects of the practice, and evince a great interest in the scientific
study of hoasca , including its botany, chemistry, and pharmacology. The medically
educated members can discuss all of these aspects with a sophistication equal
to that of any U.S.-trained physician, or other medical professional. At the
same time they do have a genuine spiritual reverence for the hoasca tea and
the experiences it evokes. The UDV places a high value on the search for scientific
truth, and sees no conflict between science and religion; most members of the
UDV express a strong interest in learning as much as possible about how the
tea acts on the body and brain. As a result of this unique circumstance, the
UDV presents an ideal context in which to conduct a biomedical investigation
of the acute and long-term effects of hoasca /ayahuasca.

Due to a fortunate
combination of circumstances, we were invited to conduct such a biomedical investigation
of long-term hoasca drinkers by the Medical Studies section of the UDV (Centro
de Estudos Medicos). This study, which was conducted by an international consortium
of scientists from Brasil, the United States, and Finland, was financed through
private donations to various non-profit sponsoring groups, notably Botanical
Dimensions, which provided major funding, the Heffter Research Institute, and
MAPS, (Multidisciplinary Association for Psychedelic Studies). Botanical Dimensions
is a non-profit organization dedicated to the study and preservation of ethnomedically
significant plants, and MAPS and the Heffter Research Institute are non-profit
organizations dedicated to the investigation of the medical and therapeutic
uses of psychedelic agents. The field phase of the study was conducted during
the summer of 1993 at one of the oldest UDV temples, the Nucleo Caupari located
in the Amazonian city of Manaus, Brasil. Subsequent laboratory investigations
took place at the respective academic institutions of some of the principle
investigators, including the Department of Psychiatry, Harbor UCLA Medical Center,
the Department of Neurology, University of Miami School of Medicine, the Department
of Psychiatry, University of Rio de Janeiro, Department of Internal Medicine,
University of Amazonas Medical School, Manaus, and the Department of Pharmaceutical
Chemistry, University of Kuopio, Finland.

Since this study
was the first of its kind, there was virtually no pre-existing data on the objective
measurement of the physical and psychological effects of ayahuasca in human
subjects. As a result, this study was in some respects a pilot study; its primary
objectives were modest, representing an effort to collect a basic body of data,
without attempting to relate the findings to either possible detrimental effects
of ayahuasca, or to possible therapeutic effects. The study had four major objectives:

Most of these
objectives were achieved, and the results have been published in various peer-reviewed
scientific journals (Grob, et al., 1996; Callaway, et al., 1994; Callaway, et
al., 1996;. Callaway, et al., 1997) Some key findings are summarized briefly
below.

Assessment of
Acute and Long-term Psychological Effects of Hoasca Teas (Grob, et al., 1996)
The subjects in all of the studies consisted of a group of fifteen healthy,
male volunteers, all of whom had belonged to the UDV for a minimum of ten years,
and who ingested hoasca on average of once every two weeks, in the context of
the UDV ritual. None of the subjects actively used tobacco, alcohol, or any
drugs other than hoasca. For some comparative aspects of the study, a control
group of fifteen age-matched males was also used; these individuals were recruited
from among the friends and siblings of the volunteer subjects, and like them
were local residents of Manaus having similar diets and socio-economic status.
None of the control subjects were members of the UDV, and none had ever ingested
hoasca tea.

The psychological
assessments, administered to both groups, consisted of structured psychiatric
diagnostic interviews, personality testing, and neuropsychological reviewuations.
Measures administered to the UDV hoasca drinkers, but not to the hoasca-niave
group, included semistructured and open-ended life story interviews, and a phenomenological
assessment of the altered state elicited by hoasca, was quantified using the
Hallucinogen Rating Scale developed by Dr. Rick Strassman in his work with DMT
and psilocybin in human subjects (Strassman, et al., 1994).

The UDV volunteers
showed significant differences from the hoasca-naive subjects in the Tridimensional
Personality Questionnaire (TPQ) and the WHO-UCLA Auditory Verbal Learning Test.
The TPQ assesses three general areas of behavior, viz., novelty-seeking, harm
avoidance, and reward dependence. With respect to novelty-seeking behaviors,
UDV members were found to have greater stoic rigidity vs exploratory excitability,
greater regimentation vs disorderliness, and a trend toward greater reflection
vs impulsivity; but there was no difference between the groups on the spectrum
between reserve and extravagance. On the harm reduction scale, UDV subjects
had significantly greater confidence vs fear of uncertainty, and trends toward
greater gregariousness vs shyness, and greater optimism vs anticipatory worry.
No significant differences were found between the two groups in criteria related
to reward-dependence.

The fifteen UDV
volunteers and the control subjects were also given the WHO-UCLA Auditory Learning
Verbal Memory Test. Experimental subjects performed significantly better than
controls on word recall tests. There was also a trend, though not statistically
significant, for the UDV subjects to perform better than controls on number
of words recalled, delayed recall, and words recalled after interference.

The Hallucinogen
Rating Scale, developed by Strassman et. al (1994) for the phenomenological
assessment of subjects given intravenous doses of DMT, was administered to the
UDV volunteers only (since control subjects did not receive the drug). All of
the clinical clusters on the HRS were in the mild end of the spectrum compared
to intravenous DMT. The clusters for affect, intensity, cognition, and volition,
were comparable to an intravenous DMT dose of 0.1 to 0.2 mg/kg, and the cluster
for perception was comparable to 0.1 mg/kg intravenous DMT; the cluster for
somatesthesia was less than the lowest dose of DMT measured by the scale, 0.05
mg/kg.

The most striking
findings of the psychological assessment came from the structured diagnostic
interviews, and the semi-structured open-ended life story interviews. The Composite
International Diagnostic Interview (CIDI) was used for the structured diagnostic
interview. None of the UDV subjects had a current psychiatric diagnosis, whereas
two of the control subjects had an active diagnosis of alcohol misuse and hypochondriasis.
Only one subject among the controls had a past psychiatric disorder that was
no longer present; an alcohol misuse disorder that had remitted two years previously.
However, prior to membership in the UDV, eleven of the UDV subjects had diagnoses
of alcohol misuse disorders, two had had past major depressive disorders, four
had past histories of drug misuse (cocaine and amphetamines), eleven were addicted
to tobacco, and three had past phobic anxiety disorders. Five of the subjects
with a history of alcoholism also had histories of violent behavior associated
with binge drinking. All of these pathological diagnoses had remitted following
entry into the UDV. All of the UDV subjects interviewed reported the subjective
impression that their use of hoasca tea within the context of the UDV had led
to improved mental and physical health, and significant improvements in interpersonal,
work, and family interactions.

Another objective of the study was to investigate whether long-term use of hoasca
resulted in any identifiable "biochemical marker" that was correlated
with hoasca consumption, particularly with respect to serotonergic functions,
since the hoasca alkaloids primarily affect functions mediated by this neurotransmitter.
Ideally, such a study could be carried out on post-mortem brains; since this
was not possible, we settled on looking at serotonin transporter receptors in
blood platelets, using [3H]-citalopram to label the receptors in binding assays.
The up-or down regulation of peripheral platelet receptors is considered indicative
of similar biochemical events occuring in the brain, although there is some
controversy about the correlation between platelet receptor changes and changes
in CNS receptors in patients receiving antidepressant medications (Stahl, 1977;
Pletscher and Laubscher, 1980; Rotman, 1980);. However, platelet receptors were
deemed suitable for the purposes of our study, as our objective was not to resolve
this controversy but simply to determine if some kind of long-term biochemical
marker could be identified. Neither did we postulate any conclusions about the
possible "adverse" or "beneficial" implications of such
a marker, if detected. We conducted the assays on platelets collected from the
same group of 15 volunteers after they had abstained from consuming the tea
for a period of one week. We also collected platelet specimens from the age-matched
controls who were not hoasca drinkers. We were surprised to find a significant
up-regulation in the density of the citalopram binding sites in the hoasca drinkers
compared to control subjects. While the hoasca drinkers had a higher density
of receptors, there was no change in the affinity of the receptors for the labelled
citalopram. The significance of this finding, if any, is unclear. There is no
other pharmacological agent which is known to cause a similar upregulation,
although chronic administration of 5-HT uptake inhibitors has been reported
to decrease both Bmax (the density of binding sites) and 5-HT transporter RNA
in rats (Hrinda 1987; Lesch et al., 1993). Increases in Bmax for the uptake
site in human platelets have been correlated with old age (Marazziti et al,
1989) and also to the dark phase of the circadian cycle in rabbits (Rocca et
al., 1989). It has been speculated (Marazziti et al, 1989) that upregulation
of 5-HT uptake sites in the aged may be related to the natural course of neuronal
decline. Although our sample size was limited, we found no correlation with
age, and the mean age of the sample was 38 years. Also, none of our subjects
showed evidence of any neurological or psychiatric deficit. In fact, in view
of their exceptionally healthy psychological profiles, one of the investigators
speculated that perhaps the serotonergic upregulation is associated, not simply
with age, but with "wisdom" -- a characteristic often found in the
aged, and in many hoasca drinkers.

Another interesting
self-experiment related to this finding was carried out by one of the investigators,
Jace Callaway, following his return to Finland after the field phase of the
study was completed. Dr. Callaway has access to Single Photon Emission Computerized
Tomography (SPECT) scanning facilities in the Department of Pharmacology at
the University of Kuopio. Suspecting that the causative agent of the unexpected
upregulation might be tetrahydroharmine (THH), Dr. Callaway took SPECT scans
of his own brain 5-HT uptake receptors prior to beginning a six week course
of daily dosing with tetrahydroharmine, repeating the scan after the treatment
period. He did indeed find that the density of central 5-HT receptors in the
prefrontal cortex had increased; when he discontinued THH, their density gradually
returned to previous levels over the course of several weeks. While this experiment
only had one subject, if it is indicative of a general effect of THH that can
be replicated and confirmed, the implications are potentially significant. A
severe deficit of 5-HT uptake sites in the frontal cortex has been found to
be correlated with aggressive disorders in violent alcoholics; if THH is able
to specifically reverse this deficit, it may have applications in the treatment
of this syndrome. These findings are especially interesting when viewed in the
context of the psychological data collected in the hoasca study (Grob, et al.,
1996). The majority of the subjects had had a previous history of alcoholism,
and many had displayed violent behavior in the years prior to joining the UDV;
virtually all attributed their recovery and change in behavior to their use
of hoasca tea in the UDV rituals. While it can be argued that their reformation
was due to the supportive social and psychological environment found within
the UDV, the finding of this long-term change in precisely the serotonin system
that is deficient in violent alcoholism, argues that biochemical factors may
also play a role

The major focus of the biochemical and physiological measurements carried out
for the study was on the acute effects subsequent to consuming hoasca tea. One
of the objectives was simply to measure the effects of hoasca on standard physiological
functions, such as heart rate, blood pressure, and pupillary diameter, subsequent
to ingestion. We found that all of these responses were well within normal parameters.
Hoasca, not surprisingly, caused an increase in pupillary diameter from baseline
(pre-dose) levels of 3.7 mm to approximately 4.7 mm at 40 minutes, which continued
to 240 minutes after ingestion at which point measurements were discontinued.
Breaths per minute fluctuated throughout the 240 minutes, from a low of 18.5
at baseline to a high of 23 breaths per minute at 100 minutes. Temperature rose
from a baseline low of 37 ° C at baseline to a high of 37.3 ° C at 240
min (although the ambient temperature also increased comparably during the course
of the experiments, which were conducted from 10:00 - 16:00). Heartrate increased
from 71.9 bpm at baseline to a maximum of 79.3 bpm by 20 minutes, decreased
to 64.5 bpm by 120 minutes, then gradually returned toward basal levels by 240
minutes. There was a concomitant increase in blood pressure; both systolic and
diastolic pressure increased to maxima at 40 minutes (137.3 and 92.0 mm Hg respectively)
over baseline values (126.3 and 82.7 mm Hg respectively) and returned to basal
values by 180 minutes. We also measured nueroendocrine response for plasma prolactin,
cortisol, and growth hormone; all showed rapid and dramatic increases over basal
values from 60 minutes (cortisol) to 90 minutes (growth hormone) to 120 minutes
(prolactin) after ingestion. The observed response, typical of serotonergic
agonists, are comparable to the values reported by Strassman & Qualls (1994)
in response to injected DMT. In our study, however, the response to oral DMT
was delayed by a factor of four or five. Dr. Russell Poland, of the Harbor-UCLA
Medical Center, carried out the neuroendocrine measurements.

The fourth objective of the study was to measure pharmacokinetic parameters
of the hoasca alkaloids in plasma following ingestion of hoasca tea, and to
correlate this to the amounts of alkaloids ingested. The UDV collaborators held
a special "preparo" to prepare the sample of hoasca that was used
forall subjects in the study. The mestres confirmed the activity in the usual
manner, via ingestion, and pronounced it active and suitable for use in the
study. Subsequent analysis by HPLC found the tea to contain, in mg/ml: harmine,
1.7; harmaline, 0.2; THH, 1.07; and DMT 0.24. Each subject received an aliquot
of tea equivalent to 2 ml/kg body weight, which was consumed in a single draught.
Based on the average body weight (74.2 ± 11.3 kg), the average dose of
tea was 148.4 ± 22.6 ml, containing an average of 35.5 mg DMT, 158.8
mg THH, 29.7 mg harmaline, and 252.3 mg harmine. These doses are above the threshold
level of activity for DMT as a psychedelic, and for harmine and THH as MAO inhibitors;
harmaline is essentially a trace constituent of hoasca tea (Callaway, et al.,
1996, 1997).

Only 12 of the
15 volunteers had sufficient plasma levels of DMT to permit pharmacokinetic
measurements, possibly due to early emesis during the course of the session.
Of these, the maximum plasma concentration (Cmax) (15.8 ng/ml) occurred at 107
minutes after ingestion, while the half-life (T1/2 was 259 minutes. THH was
measured in 14 of the 15 subjects; the Cmax was 91 ng/ml, reached at 174 min.
This compound displayed a prolonged half-life of 532 minutes, in contrast to
harmine which had a half-life of 115.6 min. The Cmax for harmine and harmaline
was 114.8 and 6.3 ng/ml, respectively, and time of maximum concentration (Tmax)
was 102 and 145 minutes, respectively. The T1/2 for harmaline could not be measured
(Callaway, et al.,1997).

In many ways this
study was conceived because of the need to collect some basic data on the physiological
and pharmacokinetic characteristics of hoasca, since none had existed previously.
The conclusions to be drawn from the results, if any, are interesting and potentially
significant, particularly in that these findings may offer a physiological rationale
for the marked improvements in psychological health that is correlated with
long-term hoasca use. Not surprisingly, the highest plasma concentrations of
DMT correlated with the most intense subjective effects; however, the psychological
measurement (Hallucinogen Rating Scale) indicated that comparable plasma levels
of injected DMT in Strassman & Qualls (1994) study were more intense than
the effects reported from the hoasca tea. One possible explanation is that THH,
by acting as a 5-HT reuptake inhibitor, may have resulted in a greater availability
of 5-HT at the synapse, and this may have competed with DMT for occupancy at
serotonergic synapses.

Another point
worthy of remark is that the activity of THH in hoasca is apparently more a
function of its inhibition of 5-HT uptake than to its action as an MAOI. THH
is a poor MAOI compared to harmine (EC50= 1.4 x 10-5 M vs 8 x 10-8 M for harmine),
and while the plasma levels for harmine are well above the EC50 values, those
for THH are well below the EC50 value for this compound as an MAOI.

Future Studies

The major objectives of the initial biomedical investigation of hoasca have
been met, including the overall objective, that of developing a basic body of
descriptive information on the physiological and psychopharmacological characteristics
of the tea. These investigations have laid the groundwork that will enable future
studies to focus on specific areas of interest. It seems clear that ayahuasca
is relatively safe; it can be taken, on a regular schedule, for months or even
years without producing any adverse effect; indeed, all of our subjects were
highly functional individuals who attribute much of their "coping"
skills to the tea and the lessons it has taught them, albiet within the doctrinal
context of the UDV. None of them showed any signs of physical disease, or neurological
or psychological deficits, indeed, many had higher scores in some of the psychometric
testing regimes than comparable control subjects who had never imbibed hoasca.
Yet many questions remain, and it is to be hoped that future investigations
will be done, and that some of the most relevant questions will be at least
partially answered. Among areas which suggest themselves for future research,
the following seem obvious:

Effect of hoasca
on women, particularly pregnant and/or lactating women. For simplicity's sake,
our initial study included only male subjects who had imbibed the tea on a regular
basis for at least ten years. Thus our sample was deliberately restricted; it
included only experienced, male hoasca drinkers, just to minimize the number
of variables. But women also drink hoasca, and moreover, most do so throughout
pregnancy and lactation; indeed, children in the UDV are baptized with a tiny
spoonful of hoasca, although they are not usually exposed to pharmacologically
active amounts until at least age 13. There are many issues here worthy of study.
For example, women claim that hoasca has positive benefits both in managing
their pregnancy, and in assisting birth; many will take hoasca during labor
to facilitate the process. The role of hoasca during pregnancy and lactation,
whether adverse or positive, is just one of a score of questions which could
be answered by followup studies using women hoasca drinkers.

Prospective studies, with children and new members. For similar reasons, our
study did not include any recent converts to the UDV, nor any children, who,
if they choose, are allowed to attend UDV sessions and imbibe smaller amounts
of hoasca as early as age 13. Nor did the study include any recent adult converts
to the UDV. Clearly, prospective studies of both groups could add a great deal
to our knowledge. In view of our finding that hoasca apparently brings about
long-term increases in serotonin uptake receptor densities, the implications
of this need to be further investigated, and prospective studies may clarify
this question. For instance, is the increase in serotonin uptake sites a consequence
of regular imbibition of hoasca, as would seem the obvious conclusion, or are
hoasca drinkers as a group biased toward those who are predisposed toward naturally
high receptor densities? And what are the implications of either finding? Similar
questions, as well as a host of sociological and developmental questions, could
be addressed in a prospective study of children of UDV members who remain in
the group and start to imbibe hoasca regularly in adolescence. An obvious question
to answer in this context would be an assessement of children and adolescents
who were exposed to hoasca in utero, to determine the impact, if any, of prenatal
hoasca exposure on their subsequent neurological and psychological development.
Another question germane to the possible long-term health benefits of regular
hoasca use is that of whether the practice might prove to be prophylactic against
alcohol and drug misuse for adolescents who consume the tea within the UDV structure.

Brain imaging and electrophysiological studies. To the degree that facilities
can be made available, brain imaging and electrophysiological studies of the
acute and chronic effects of hoasca would further fill in the picture of its
pharmacological characteristics.

Therapeutic applications of hoasca in treatment of alcoholism and other forms
of substance misuse. The experience of UDV members, recounted in the structured
"life-story" interviews, would seem to indicate that hoasca has real
potential as a therapeutic agent in treating substance misuse and/or alcoholism
as well as other psychopathologies. Most of the subjects interviewed were involved
with substance misuse prior to joining the UDV, and have since ceased. Most
attribute their recovery to the tea; it would seem that confirmation of their
experience and further information could be collected relatively easily, perhaps
through a prospective study using recent converts to the UDV with prior involvement
with substance misuse or other addictive disorders.

Immunomodulatory effects of hoasca. Another parameter that could be easily assessed,
that may have important implications for the long-term health effects of hoasca,
is the question of its possible effects on the immune system. Hoasca may be
an immunostimulant, and thus potentially beneficial in maintaining resistance
to disease; on the other hand, it could be an immunosuppressant, and this would
also have serious implications for long-term or frequent use. Although hoasca
tea is customarily used as a ritual sacrament rather than a medicine, anecdotal
reports suggesting that hoasca may facilitate recovery from serious illnesses
such as cancer, and well-designed studies are needed to investigate this question.
One possibility is that discontinuation of the use of alcohol, tobacco, and
drugs of misuse, as is common in UDV members, may contribute to long-term salutory
effects on health.

Prospective and epidemiological study of hoasca and Parkinson's disease. Earlier
in this century, harmine, then known as banisterine, was investigated for its
potential utility in the treatment of postencephalitic parkinsonism (Sanchez-Ramos,
1991). Despite some initially encouraging results in early clinical trials,
further explorations of this promising pharmacotherapy were abandoned in the
1930's in favor of synthetic drugs, without really resolving the question of
whether harmine may have some benefits as an anti-parkinson's agent. Both prospective
and epidemiological studies of the incidence of parkinson's among UDV members,
compared to the general population, could shed some light on the possible applications
of harmine or other ß-carbolines in the treatment of parkinson's disease.

Summary

Ayahuasca, or hoasca, whether known by these names, or any of numerous other
designations, has long been a subject of fascination to ethnographers, botanists,
psychopharmacologists, and others with an interest in the many facets of the
human relationship with, and use of, psychoactive plants. With its complex botanical,
chemical, and pharmacological characteristics, and its position of prime importance
in the ethnomedical and magico-religious practices of indigenous Amazonian peoples,
the investigation of ayahuasca in its many aspects has been an impetus to the
furtherence of our scientific understanding of the brain/mind interface, and
of the role that psychoactive plant alkaloids have played, and continue to play,
in the quest of the human spirit to discover and to understand its own trancendent
nature.

Now, the process
which has unfolded in Western culture since Richard Spruce first reported on
ayahuasca use among the Indians of the Norwthwest Amazon in 1855 (Anon, 1855;
Spruce, 1873) has reached a new stage. Ayahuasca has emerged from the Amazonian
jungles where it has remained cloaked in obscurity for thousands of years, to
become the sacramental vehicle for new syncretic religious movements that are
now diffusing from their center of origin in Brasil to Europe, the United States,
and throughout the world. As the world observes this process unfolding (with
joyous anticipation for some, and with considerable trepidation for others),
the focus for the scientific study and understanding of ayahuasca has shifted
from the ethnographer's field notes and the ethnobotanist's herbarium specimens,
to the neurochemist's laboratory and the psychiatrist's examining room. With
the completion of the first detailed biomedical investigation of ayahuasca,
science now has the basic corpus of data needed to ask further questions, regarding
the pharmacological actions, the toxicities and possible dangers, and the considerable
potential ayahuasca has to heal the human mind, body, and spirit. Humanity's
relationship with ayahuasca is a long-term commitment, expressed on an evolutionary
timescale, that has already taught us much, and from which we can still learn,
provided we have the courage, and the tools, to ask the right questions.